Abnormalities of corticosteroid and androgen metabolism have been reported in schizophrenia, but there have been no published studies of estrogen metabolism in this disease. We carried out pilot studies of 14C-estradiol metabolism in 5 young schizophrenics and found a marked abnormality: an increased ratio of estriol (E3) to 2-methoxyestrone (2-Me0-E1) among the urinary glucuronide metabolites. Though this abnormality resembles that of hypothyroidism, the patients were clinically euthyroid and their 14C-cortisol metabolism showed a perfectly normal euthyroid pattern. This "hypothyroid-like" abnormality of estradiol metabolism in the absence of hypothyroidism is specific for schizophrenia in our experience; no other patients show such a pattern. We propose to confirm the existence of specifically abnormal estradiol metabolism in schizophrenia and to determine whether its prevalence differs in various groups of schizophrenics (e.g. acute vs subchronic, particular behavioral or psychological subgroups, etc.). For this purpose we will use the simplified and rapid, but highly specific, radiometric procedures described by Fishman et al. (PNAS 77:4957, l980): the extent of oxidation of injected stereospecifically labeled (2-3H)-estradiol or (16Alpha-3H)-estradiol tracers measures the respective magnitudes of the 2-hydroxylation and 16Alpha-hydroxylation pathways of estradiol metabolism of which 2-Me0-E1 and E3 are the respective end-products. The ratio of 2-hydroxylation to 16Alpha-hydroxylation in 30 acute and 30 subchronic schizophrenics, carefully selected according to pre-established criteria, will be compared with the known normal values. Demonstration of an abnormal ratio in some or all schizophrenics may cast light on the pathophysiology of schizophrenia, and may lead to new approaches to prevention and/or treatment.